Cartilage tissue is composed of a matrix and chondrocytes. Among these, collagen fibers (collagen, proteoglycan) of the matrix, together with noncollagenous proteins, absorb and discharge water into/from cartilage to thereby play an important role in maintenance of physical properties unique to the cartilage. Damage of cartilage tissue is largely observed in joint diseases, and cartilage tissue of joints is broadly subdivided into four zones, that is, the outermost superficial tangential zone, a middle zone, a deep zone and a calcified zone (Clouet J et al., Drug Discovery Today (2009) 14:19/20, 913-925). The superficial tangential zone is a region with a relatively low proportion of the matrix, in which collagen fibers are densely arranged along the joint surface and chondrocytes having thin and flat cellular morphology are present, and which absorbs shearing force of articular movement. The middle zone is thicker than the superficial tangential zone, is composed of thick collagen fibers and spherical chondrocytes, and serves to withstand a load, due to having a high proportion of the matrix containing proteoglycan and water. The deep zone is rich in proteoglycan and noncollagenous proteins in conjunction with the highest content of matrix components but the lowest water content, and serves to impart the stability of tissue through vertical arrangement of relatively small numbers of chondrocytes close to the spherical shape and collagen fibers. The calcified zone has a specific structure known as tidemark and functions to fix cartilage tissue to bone tissue.
Damage of cartilage tissue constituting joints results in the onset of arthritis which is accompanied by swelling, warmth and pain. The onset of arthritis is irrespective of races and is classified into approximately 100 types depending on the pathogenic cause thereof. The most common form of arthritis is osteoarthritis, a degenerative joint disease which primarily caused by aging. Other examples of arthritis include rheumatoid arthritis and psoriatic arthritis which are autoimmune diseases, and septic arthritis caused by infections. In particular, degenerative arthritis is a representative disease of advanced age groups, and aging of joints is mainly responsible for the pathogenesis of degenerative arthritis. Further, since the incidence of degenerative arthritis is also due to a combined interaction of various factors, such as genetic factors, imbalanced nutrition, a lack of exercise, immoderate exercise or injury, behavior of applying a heavy load to joints, for example, overwork or habitual bad posture, and overload due to obesity, degenerative arthritis is also a disease with high frequency observed among young people (Gegout P P et al., Joint Bone Spine (2008) 669-671).
Weakening of joint-supporting tissue due to trauma or degenerative alteration leads to injury of cartilage tissue which serves to absorb impact, thus increasing bone-to-bone friction to cause pain and inflammation. Inflammation accelerates the formation of osteophytes around joints, which restricts mobility of joints and causes more severe pain.
Arthritis is a disease with a high pathogenic incidence among broad age groups and damaged tissue does not readily undergo spontaneous regeneration or restoration. Therefore, arthritis is responsible for long-term restriction of social activity of patients and deterioration of a quality of a patient's life.
Currently available therapeutic measures are broadly divided into conservative therapies such as exercise therapy including weight control, dietetic therapy, injection therapy and pharmacotherapy; and surgical therapies such as tissue regeneration using growth factors, implantation using artificially cultured cells, and artificial joint replacement which is applied when joints are severely damaged (Clouet J et al., Drug Discovery Today (2009) 14:19/20, 913-925).
Exercise therapy within the range of applying no heavy load to joints has an effect of strengthening the joint's surrounding tissue to retard further symptomatic aggravation, but provides no fundamental regeneration of damaged tissue and has difficulty of being carried out due to pain when the condition of illness is severe.
For the purpose of promoting tissue regeneration of joints or relieving inflammation, there have been used glucosamine or chondroitin which is a constituent component of cartilage, fish oil having an anti-inflammatory action, and other herbal pharmaceutical compositions (Derfoul A et al., Osteoarthritis Cartilage (2007) 15, 646-655; Tiraloche G et al., Arthritis Rheum. (2005) 52, 1118-1128; McAlindon T E et al., JAMA (2000) 283 (11): 1469-147; and Zainal Z et al., Osteoarthritis Cartilage (2009) 17(7): 896-905).
Further, a method of injecting hyaluronic acid (HA) which is a joint synovial fluid component has also been used for the relief of pain and prevention of symptomatic aggravation by reducing friction of damaged regions (Waddell D D et al., Arthroscopy (2010) 26(1):105-11; and Wang C T et al., J. Bone Joint Surg. Am. (2004) 86-A 538-545).
Although some of these conservative therapies have been reported to have beneficial therapeutic effects, their pain relief or therapeutic effects are insignificant or the mechanism thereof is not fully understood. Therefore, there is a need for further inspection from the viewpoint of therapeutic applications of such therapies (McAlindon T E et al., JAMA (2000) 283 (11): 1469-147).
For the relief of inflammation or pain, aspirin, acetaminophen, or various nonsteroidal antiinflammatory drugs (NSAIDs) and steroidal drugs such as cortisone have been used. However, these pharmacotherapies are not fundamental therapies which are capable of achieving the restoration of damaged tissue. In addition, long-term administration of such drugs has reportedly adverse side effects such as gastrointestinal, tissue or bone damage (Clouet J et al., Drug Discovery Today (2009) 14:19/20, 913-925; Glass G G Dis. Mon. (2006) 343-362; Zhang W et al., Ann. Rheum. Dis. (2004) 63, 901-907); Frampton J E et al., Drugs (2007) 67(16):2433-72; and McDonough A L. Phys Ther. (1982) 62(6): 835-9.).
For the purpose of regeneration or restoration of damaged cartilage tissue, use of a composition containing apigenin, or a growth factor or a portion thereof, such as FGF, BMPs (BMP7/OP-1) or TGFβ1, has been contemplated (Clouet J et al., Drug Discovery Today (2009) 14:19/20, 913-925; Shi S et al., J. Biol. Chem. (2009) 284 (1): 6697-6704; and Moore E E et al., Osteoarthritis Cartilage (2005) 13, 623-631). However, since there is limitation to carry out direct and repeated infusion with a growth factor composed of high molecular weight protein into arthritis patients, the practical application of such a growth factor to patients requires further investigation for a delivery method thereof.
When the above-mentioned conservative therapies provide no therapeutic effects or intense pain continues, a surgical therapy involving replacement of damaged joints with artificial joints is used. However, an artificial joint has a limited lifespan of about 10 years, so re-surgery is necessary where appropriate. In this case, re-surgery has limitations due to difficulty in removal of artificial joints stenosed to bone, a need for implantation of larger artificial joints, and a need for more extensive peripheral bone tissue. For these problems, the application of artificial joint replacement to younger people should be made with more care.
With the advancement of artificial cell culture techniques, it has recently been reported methods including artificial culture of chondrocytes from multipotent stem cells or autologous mesenchymal stem cells and implantation of the cultured chondrocytes (Csaki C et al., Ann Anat. (2008) 190(5): 395-412). Unfortunately, the chondrocyte implantation still has a large number of problems to be solved, in terms of being not easy to obtain a sufficient number of autologous cells, in conjunction with technical and cost problems associated with application thereof to numbers of patients, such as adhesion of implanted cells, regeneration efficiency and safety.
As we enter an aging society, the advanced age population suffering from arthritis is steadily increasing. Further, the incidence of joint diseases due to immoderate exercise, imbalanced nutrition, obesity or the like is also increasing among younger age groups. In order to reduce consequent economic loss and social expenses and improve life quality of the advanced age population, there is an urgent need for the development of an advanced anti-arthritis drug, which is capable of achieving more convenient, safe and fundamental regeneration and restoration of arthritis-damaged cartilage tissue, instead of conventional conservative dietetic therapy or pharmacotherapy to relieve inflammation or pain, surgical therapy such as artificial joint replacement, or implantation of artificially cultured chondrocytes.